DMF: 27028
OXALAN®, used in combination with infusional 5-fluorouracil(5-FU)/leucovorin, is indicated for:
OXALAN® should not be administered to patients:
– with a history of known allergy to oxaliplatin or other platinum compounds or to any ingredient in the formulation or component of the container.
– who are breast-feeding.
– who are pregnant.
– with severe renal impairment (creatinine clearance ClCr < 30 ml/min).
– Hypersensitivity, anaphylactic reactions, and/or allergic reactions are reported with the use of OXALAN®. These can occur within minutes of OXALAN® administration, and can include rash, urticaria, erythema, pruritus, laryngospasm and, rarely, bronchospasm and hypotension. Allergic reactions can occur during any cycle. Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to OXALAN®, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. These reactions are usually managed with epinephrine, corticosteroid, and antihistamine therapy. OXALAN® rechallenge is contraindicated.
– OXALAN® is associated with two types of neuropathies:
– Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.
– OXALAN® has been associated with pulmonary fibrosis, which may be fatal. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, OXALAN® should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
– Hepatotoxicity with the use of OXALAN® plus 5-FU/LV has been occurred. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in cases of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases. There is evidence that OXALAN® causes liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of the liver, which on liver biopsy is manifested as peliosis, nodular regenerative hyperplasia, and perisinusoidal fibrosis.
– OXALAN® may lead to irreversible infertility. It is recommended that men treated with OXALAN® should not procreate during treatment and for up to 6 months after the end of treatment; they should also seek advice about sperm storage prior to treatment.
– Patients receiving OXALAN® plus 5-FU/leucovorin and requiring oral anticoagulants may require close monitoring.
– Cases of QT prolongation and Torsade de Pointes have been reported. QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal. Caution should be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, oxaliplatin treatment should be discontinued.
– OXALAN® treatment resulting in an increased risk of dizziness, nausea and vomiting, and neurologic gait and balance disorders may have influence on the ability to drive and operate machinery.
– Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic antiemetic therapy. Dehydration, ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and even renal disorders, may be associated with severe diarrhea/emesis, particularly when combining OXALAN® with 5-FU. In rare cases, colitis, including Clostridium difficile diarrhea, have occurred. Patients must be adequately informed of the risk of diarrhea/emesis after OXALAN®/5-FU administration in order to contact urgently their treating physician for appropriate management. OXALAN® treatment can cause intestinal ischaemia, duodenal ulcer (DU) and potential complications, such as duodenal ulcer haemorrhage and perforation, which can be fatal. In case of duodenal ulcer and intestinal ischaemia, OXALAN® treatment should be discontinued and appropriate measures taken.
– Patients must be adequately informed of the risk of neutropenia after OXALAN®/5-FU administration in order to contact urgently their treating physician for appropriate management. Cases of febrile neutropenia (including fatal cases) have been reported. If neutropenia or febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 × 109/L, a single temperature of > 38.3°C or a sustained temperature of > 38°C for more than one hour) occurs, OXALAN® must be discontinued until improvement or resolution, and the dose of OXALAN® should be reduced at subsequent cycles, in addition to any 5-FU dose reductions required.
– Hemolytic Uremic Syndrome (HUS) is a life-threatening side effect. OXALAN® should be discontinued at the first signs of any evidence of microangiopathic hemolytic anemia, such as rapidly falling hemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or lactate dehydrogenase (LDH). Renal failure may not be reversible with discontinuation of therapy and dialysis may be required.
– Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes. If any of these events occurs, OXALAN® should be discontinued.
– Rhabdomyolysis has been reported in patients treated with OXALAN®, including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, OXALAN® treatment should be discontinued. If rhabdomyolysis is confirmed, appropriate measures should be taken. Caution is recommended if medicinal products associated with rhabdomyolysis are administered concomitantly with OXALAN®.
– In case of OXALAN® extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.
OXALAN® is only for adults. Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.
Dosage
Administer OXALAN® in combination with 5-FU/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):
Day 1: OXALAN® 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-FU 400 mg/m2 intravenous bolus given over 2-4 minutes, followed by 5-FU 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-FU 400 mg/m2 intravenous bolus given over 2-4 minutes, followed by 5-FU 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. The administration of OXALAN® does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.
Very common (more than one out of 10 patients):
– Hepatic enzyme increase – Blood alkaline phosphatase increase – Blood bilirubin increase – Blood lactate dehydrogenase increase – Weight increase (adjuvant setting) – Anaemia – Neutropenia – Thrombocytopenia – Leukopenia – Lymphopenia – Peripheral sensory neuropathy – Sensory disturbance – Dysgeusia – Headache – Dyspnoea – Cough – Epistaxis – Nausea – Diarrhoea – Vomiting – Stomatitis /Mucositis – Abdominal pain – Constipation – Skin disorder – Alopecia – Back pain – Anorexia – Hyperglycaemia – Hypokalaemia – Hypernatraemia – Infection – Fatigue – Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism. – Asthenia – Pain – Injection site reactions including local pain, redness, swelling and thrombosis have been reported. Extravasation may also result in local pain and inflammation, which may be severe and lead to complications, including necrosis, especially when oxaliplatin is infused through a peripheral vein – Very common allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Common allergic reactions include skin rash (particularly urticaria), conjunctivitis and rhinitis.
Common (less than1 out of 10 patients):
– Blood creatinine increase
– Weight decrease (metastatic setting) -Febrile neutropenia – Dizziness – Motor neuritis – Meningism – Conjunctivitis – Visual disturbance – Hiccups – Pulmonary embolism – Dyspepsia -Gastro esophageal reflux – Gastrointestinal hemorrhage – Rectal haemorrhage -Haematuria – Dysuria – Micturition frequency abnormal – Skin exfoliation (i.e. Hand & Foot syndrome) – Rash erythematous – Rash – Hyperhidrosis – Nail disorder – Arthralgia – Bone pain – Dehydration – Hypocalcaemia – Rhinitis – Upper respiratory tract infection – Neutropenic sepsis – Haemorrhage – Flushing – Deep vein thrombosis – Hypertension – Depression – Insomnia – Fall
Uncommon (less than1 out of 100 persons):
– Ototoxicity – Ileus – Intestinal obstruction – Metabolic acidosis – Sepsis – Nervousness
Rare (less than1 out of 1000 persons)
– Immunoallergic thrombocytopenia – Haemolytic anaemia – Disseminated intravascular coagulation (DIC), including fatal outcomes – Dysarthria – Reversible Posterior Leukoencephalopathy syndrome (RPLS, or PRES) – Visual acuity reduced transiently – Visual field disturbances – Optic neuritis – Transient vision loss – reversible following therapy discontinuation – Deafness – Interstitial lung disease sometimes fatal – Pulmonary fibrosis – Colitis including clostridium difficile diarrhea – Pancreatitis
Very rare (less than1 out of 10000 persons)
– Liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of liver, or pathological manifestations related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis -Portal hypertension and/or increased transaminases -Acute tubular necrosis, acute interstitial nephritis and acute renal failure
Not known (frequency cannot be estimated from the available data)
-Haemolytic uremic syndrome -Autoimmune pancytopenia – Pancytopenia – Secondary leukemia – Convulsion -Laryngospasm -Pneumonia and bronchopneumonia, including fatal outcomes – Intestinal ischemia, including fatal outcomes – Gastrointestinal ulcer and perforation, which can be fatal – Oesophagitis – Focal nodular hyperplasia -Hypersensitivity vasculitis -Rhabdomyolysis, including fatal outcomes -Septic shock, including fatal outcomes -QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal – Acute coronary syndrome, including myocardial infarction and coronary arteriospasm and angina pectoris in patients treated with Oxaliplatin in combination with 5-FU and bevacizumab -Ischemic or haemorrhagic – cerebrovascular disorder
No P450-mediated drug-drug interactions are anticipated in patients. Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied. Interactions between OXALAN® and other drugs are as follow:
Risk X (Avoid Combination): BCG, Clozapine, Natalizumab, Pimecrolimus, Tofacitinib, Vaccines (Live), Tacrolimus (Topical)
Risk D: (Consider therapy modification): Echinacea, Leflunomide, Roflumilast, Taxane Derivatives, Topotecan
Risk C: (Monitor therapy): Cardiac Glycosides (Exceptions: Digitoxin), Coccidioidin Skin Test, Denosumab, Sipuleucel-T, Trastuzumab, Vaccines (Inactivated), Vitamin K Antagonists (eg, warfarin)
OXALAN® is likely to be lethal and/or teratogenic to the human foetus at the recommended therapeutic doses. OXALAN® is contraindicated in pregnancy and lactation. As with other cytotoxic agents, effective contraceptive methods should be taken in potentially fertile patients (male and female) prior to initiating chemotherapy with OXALAN®.
– Keep the medicine in the box until it is consumed.
– store the medicine at temperatures below 30°C and stored away from light and moisture.
– Keep the medicine out of the reach of children and pets.
– Any unused product, as well as the materials used for reconstitution, dilution and administration, must be destroyed according to hospital standard procedures relative to cytotoxic agents in accordance with the legislative provisions in force for the disposal of toxic waste
– Solution must be clear and without any particle otherwise do not use it.
– It is forbidden to sell this drug without prescription.